Positron Emission Tomography (PET) is a molecular imaging modality that utilizes radiolabeled tracer molecules to target, image and quantify biological processes in vivo. PET tracers can be used to study disease mechanisms, to develop novel diagnostics and therapeutics, detect early stage disease, and monitor response to therapy. Due to low density of receptors in the CNS (e.g. picomole/gram tissue receptor concentration), it is critical to synthesize PET radioligands with high specific activity (SA) for n vivo neuroimaging. In particular, very high specific activity of radioligands (e.g. [F-18]Fallyprid) is needed to obtain good image contrast in brains of small animals without inducing any pharmacological effect. The lack of a robust, easy-to-use radiosynthesizer capable of the production of diverse radioligands with high SA remains the bottleneck in accelerating the translation of new radiotracers into brain imaging diagnostics or routine tools for study of CNS disorders and treatments. Microfluidic platforms for radiosynthesis have been actively pursued during the past several years due to a number of intrinsic advantages compared to conventional setups. One of these is the ability to manipulate very tiny volumes (down to the sub-microliter regime). It is hypothesized that volume reduction can reduce the total amount of fluorine-19 contamination in the reaction and thereby result in higher specific activity tracers. In preliminar experiments, the specific activity of [F-18]FDG produced on EWOD microfluidic chips was found to be significantly higher (25x) than that produced on conventional apparatus. Building upon this result, a new technology platform for the preparation of high specific activity tracers is proposed In Aim 1, the radiosynthesis of [F-18]Fallypride, an important tracer that targets low-abundance D2/D3R receptors in the brain will be developed on EWOD chips, and its specific activity compared to that of macroscale production, to extend the [F-18]FDG results to tracers targeting the CNS. In Aim 2, the geometry of the EWOD chip will be systematically varied to understand the factors that most strongly affect the fluorine-19 content and hence the specific activity. Based on the findings of Aim 2, an optimized EWOD chip will be developed in Aim 3 to produce high specific activity probes. Subsequently, [F-18]Fallypride synthesis will be optimized for this new chip and the effect of high and low specific activity of [F-18]Fallypride will be investigated n small animal imaging. It is expected that the results for [F-18]Fallypride will be generalizable toa large number of other tracers. This proposal will result in the development of a proof-of-concept prototype for high specific activity PET tracer production that could serve a critical role in more rapidly translating new diagnostics and therapies to clinical practice via molecular imaging with PET in small animals. PUBLIC HEALTH RELEVANCE: The proposed research will provide a technology uniquely suited for producing tracers with very high specific activity for imaging with positron emission tomography (PET). Unlike in many other parts of the body, the biology of the central nervous system (CNS) including the brain requires PET tracers to have very high specific activity for successful imaging without interfering with the physiology of the patient. This technology will provide a critical tool in the research and development of new diagnostics and therapies for CNS disorders, accelerating the translation of research from basic biology into human health.